Human T-cell leukemia/lymphoma virus (HTLV-I) is a unique, exogenous, horizontally transmitted retrovirus which has been isolated from patients with certain T-cell leukemias and lymphomas in southern Japan, the Caribbean basin, southeastern United States and elsewhere. The virus is capable of rapid transformation of T-cells in vitro, but the mechanism(s) of transformation both in vitro and in vivo is unclear. Previous avian and mammalian retrovirus isolates have been demonstrated to induce transformation by two different mechanisms; directly through the protein product encoded by an oncogene included in the retroviral genome or by alteration of the regulation of operative cellular loci by integration adjacent to normal cellular genes that are capable of causing transformation, when expressed (or repressed) in an unscheduled manner. Since HTLV-I does not carry an oncogene related to human DNA, the latter mechanism is a distinct possibility. We have utilized somatic cell hybrids constructed between rodent cells and various HTLV-I-infected cell lines to study the processes and consequences of HTLV-I chromosomal integration, as well as certain biologic phenomena observed in HTLV-I-infected cells. Integration in primary tumors was found to be monoclonal, but dynamic with as many as 20 secondary HTLV integrations occurring subsequent to tumorigenesis. The primary integration site of two HTLV-I-associated tumors have been chromosomally mapped and their sites are being examined from two perspectives: (1) to determine the specificity (or not) of targeted HTLV-I integration, and (2) the role of the chromosomal "neighborhood" of integration in the neoplastic transformation process.